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Abstract: FR-PO163

Pirfenidone Confers Effective Prophylaxis of Renal Ischaemia Reperfusion Injury

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Bowen, Timothy, Cardiff University School of Medicine, Cardiff, Cardiff, United Kingdom
  • Khalid, Usman, University Hospital of Wales, Cardiff, Cardiff, United Kingdom
  • Foxwell, David A., Cardiff University School of Medicine, Cardiff, Cardiff, United Kingdom
  • Andrews, Robert, Cardiff University School of Medicine, Cardiff, Cardiff, United Kingdom
  • Pino-Chavez, Gilda, University Hospital of Wales, Cardiff, Cardiff, United Kingdom
  • Chavez, Rafael E., University Hospital of Wales, Cardiff, Cardiff, United Kingdom
  • Fraser, Donald, Cardiff University School of Medicine, Cardiff, Cardiff, United Kingdom
Background

Pre-clinical models show that direct or indirect ischemic preconditioning (IPC) confer protection from subsequent ischemic acute kidney injury (AKI). Nevertheless, IPC has not proved effective in clinical trials involving individuals at elevated risk of AKI. Using a drug repurposing approach, we have identified six compounds suitable for clinical testing to detect evidence of IPC-like benefit.

Methods

We used RNA sequencing to analyse the renal transcriptome following direct and indirect IPC in a rat bilateral IRI model. A common protective signature was identified, and Ingenuity Pathway Analysis (IPA) was performed to predict drug repurposing candidates that would confer similar changes in gene expression profiles. The effects of predicted candidates were then evaluated in vivo.

Results

Three repeated cycles of two minutes ischaemia followed by five minutes reperfusion conferred optimum benefit with either direct or indirect pulsatile IPC. Subsequent whole kidney transcriptomic profiling of sham, IRI, direct-IPC/IRI and indirect-IPC/IRI (n = 6 per group) mapped to 16,780 unique genes, of which 2,193 were differentially expressed between IRI and sham. IPA attributed these observations to an acute renal failure phenotype (p = 1.3 x 10-27) and renal proximal tubular toxicity (p = 5.1 x 10-15). Master regulators and pathways identified within inflammatory response, oxidative stress and cell cycle were diminished following both direct and indirect IPC. Based on comparison with transcriptomic information available for over 23,500 biological drugs and chemical compounds, IPA identified six repurposing candidates with potential for clinical testing for IRI prophylaxis: AG490, diphenyleniodonium, pirfenidone, pyrrolidine dithiocarbamate, SP600125 and U0126, which were then evaluated further in vivo. All exhibited functional benefits when administered as a single prophylactic dose pre-IRI, but pirfenidone produced the most effective prophylaxis.

Conclusion

We have identified a protective gene expression signature common to direct and indirect IPC that provides novel mechanistic insights into the pathology of IRI injury and IPC protection. Using this dataset, computational transcriptional analysis has identified candidate drugs for repurposing for use in IRI prophylaxis, of which pirfenidone performed best.